Clean Steam Systems 228
清洁蒸汽系统228

Solvents 228
溶剂228

Medical Grade Gases 229
医用级气体229

Examples of Significant and/or Trend of Deficiencies 229
显著和/或缺陷趋势的例子229

Recent Regulatory Findings 230
最近的监管调查结果230

References 230
参考资料230

The Production System 233
生产系统233

Michele Conway and Robert Ferer
米歇尔·康威 （Michele Conway） 和罗伯特·费勒 （Robert Ferer）

Training/Qualification of Personnel 235
人员培训/资格认证235

Control System for Implementing Changes in Process 236
用于实施流程变更的控制系统236

Adequate Procedure and Practice for Charge-in of Components 238 Formulation/Manufacturing at Not Less Than 100% 239
组件充注的适当程序和实践 238 配方/制造不低于 100%239

Identification of Equipment with Contents, and Where
识别带内容物的设备，以及在哪里

Appropriate Phase of Manufacturing and/or Status 240
适当的制造和/或状态阶段240

Validation and Verification of Cleaning/Sterilization/
清洁/灭菌的验证和验证/

Depyrogenation of Containers and Closures 241
容器和瓶盖的去热原241

Calculation and Documentation of Actual Yields and
实际产量的计算和记录以及

Percentage of Theoretical Yields 243
理论产量百分比243

Contemporaneous and Complete Batch Production
同时和完整的批量生产

Documentation 244
文档244

Established Time Limits for Completion of Phases of Production 245 Implementation and Documentation of In-Process Controls,
确定完成生产阶段的时限 245 过程控制的实施和记录，

Tests, and Examinations (e.g„ pH, adequacy of mix, weight variation, clarity) 246
测试和检查（例如“pH 值、混合物的充分性、重量变化、澄清度）246

Justification and Consistency of In-Process Specifications
过程中规范的合理性和一致性

and Drug Final Specifications 247
和药物最终规格247

Prevention of Objectionable Microorganisms in Non-Sterile
防止非无菌中的有害微生物

Drug Products 248
药品248

Adherence of Preprocessing Procedures (e.g., set-up, line
遵守预处理程序（例如，设置、生产线

clearance, etc.) 249
清仓等）249

Equipment Cleaning and Use Logs 250
设备清洁和使用日志250

Master Production and Control Records/Batch Production
主生产和控制记录/批量生产

and Control Records 251
和控制记录251

Process Validation, Including Validation and Security of
流程验证，包括

Computerized or Automated Processes 252
计算机化或自动化流程252

Change Control: The Need for Revalidation Evaluated 254
变更控制：评估重新验证的必要性254

Documented Investigation into any Unexpected Discrepancy 255
对任何意外差异的记录调查255

References 256
参考资料256

The Packaging and Labeling System 259
包装和标签系统259

Jeanne Moldenhauer
珍妮·莫尔登豪尔

Areas Expected to be Covered in an Inspection 259
检查预期覆盖的区域259

Considerations for Assessing Compliance for these Systems 261
评估这些系统的合规性的注意事项 261

Evidence of Written Procedures 261
书面程序的证据261

Training and Qualification of all Affected Personnel 261
所有受影响人员的培训和资格认证261

Procedure for Acceptance of Packaging and Labeling
包装和标签的验收程序

Materials 261
材料261

Effective Change Control System for Implementing
用于实施的有效变更控制系统

Changes in Packaging and Labeling Operations 262
包装和贴标作的变化262

Adequate Storage for Labels and Labeling (both approved and those returned after Issuance) 262
标签和标签的充足存储空间（已批准和签发后退回的标签和退回的标签）262

Control of Labels that are Similar in Size, Shape, and Color for Different Products at the Site 263
控制 Site263 中不同产品的大小、形状和颜色相似的标签

If Cut Labels are used for Finished Products for
如果切割标签用于成品

Immediate Containers that are Similar in
在

Appearance without Some Type of 100% Electronic or
外观没有某种类型的 100% 电子或

Visual Verification System or Use of Dedicated Lines 263
目视验证系统或使用专用线路 263

Verification that Gang Printing of Labels is Not
验证标签的 Gang Printing 不是

Performed, Unless the Labels are Differentiated by
执行，除非标签的区分方式

Size, Shape or Color 263
大小、形状或颜色263

Control Procedures are Established and Followed if
在以下情况下建立并遵循控制程序

Filled Unlabeled Containers are Produced that are
已装满的未贴标签容器是

Later Labeled under Multiple Private Labels 264
后来在多个自有品牌下标记264

Adequate Packaging Records are Available that Include
提供足够的包装记录，包括

Specimens of All Labels Used for Each Product and Lot 264
用于每个产品和 Lot264 的所有标签的样本

Control Procedures are Established and Followed for
制定并遵循控制程序

Issuance of Labeling, and there is Appropriate
发布标签，并且有适当的

Examination of Issued Labels and Reconciliation of
已发布标签的审查和对账

Used Labels 264
二手标签264

Examination of Labeled Finished Product is Conducted 264
对贴标签的成品进行检查264

Adequate Inspection (proofing) of Incoming Labeling
对进货标签进行充分检查（打样）

Materials 265
材料265

Appropriate Use of Lot Numbers on Labels, and
在标签上适当使用批号，以及

Destruction of Excess Labeling Bearing Lot or
销毁超额标签 Bearing Lot 或

Control Numbers 265
控制号码265

Physical and/or Spatial Separation Exists Between Different Labeling and Packaging Lines 265
不同的贴标和包装线之间存在物理和/或空间上的分离265

Monitoring of Printing Devices Associated with
监视与 关联的打印设备

Manufacturing Lines is Conducted 265
进行生产线265

Line Clearance and Inspection is Performed and
执行线路清理和检查，然后

Documented 266
记录266

Adequate Expiration Dates are Present on the Label 266
标签上有适当的有效期266

Conformance to Tamper-Evident Packaging (TEP) Requirements, as Required per 21 CFR §211.132
符合 21 CFR §211.132 的要求防篡改包装 （TEP） 要求

and Compliance Policy Guide No. 7132a. 17 266
以及合规政策指南编号 7132a. 17266

Appropriate Validation of Packaging and Labeling
包装和标签的适当验证

Operations is Conducted including Validation
执行包括验证在内的作

and Security of Computerized Processes 266
和计算机化进程的安全性266

Documented Investigations are Performed for any
对任何

Unexpected Discrepancy 266
意外差异266

Examples of Significant and/or Trend of Deficiencies 267
显著和/或缺陷趋势的例子267

Recent Regulatory Findings 267
最近的监管调查结果267

Reference 267
编号267

The Laboratory System 269
实验室系统269

Jeanne Moldenhauer
珍妮·莫尔登豪尔

Areas Expected to be Covered in an Inspection 269
检查预期覆盖的区域269

Considerations for Assessing Compliance for these
评估这些合规性的注意事项

Systems 271
系统271

Evidence of Written Procedures 271
书面程序的证据271

Training and Qualification of all Affected Personnel 271
所有受影响人员的培训和资格认证271

Adequacy of Staffing for Laboratory Operations 271
实验室运营人员配备是否充足271

Adequacy of Equipment and Facility for Intended Use 272 Calibration and Maintenance Programs for Analytical
预期用途的设备和设施是否充足 272 分析校准和维护计划

Instruments and Equipment 273
仪器设备273

Validation and Security of Computerized or Automated
计算机化或自动化的验证和安全性

Processes 274
进程274

Reference to Standards, Source, Purity and Assay, and
参考标准品、来源、纯度和测定方法，以及

Tests to Establish Equivalency to Current Official
确定与当前官方等效性的测试

Reference Standards, as Appropriate 274
参考标准（视情况而定）274

System Suitability Checks on Chromatographic Systems
色谱系统的系统适用性检查

(e.g., GC or HPLC) 275
（例如 GC 或 HPLC）275

Specifications, Standards, and Representative
规格、标准和代表

Sampling Plans 275
抽样计划275

Adherence to the Written Methods of Analysis 275
遵守书面分析方法275

Validation or Verification of Analytical Methods 275
AnalyticalMethods275 的验证或验证

Control System for Implementing Changes in Laboratory
用于实施实验室变化的控制系统

Operations 276
运营276

Required Testing is Performed on the Correct Samples 277
对正确的样品执行所需的测试277

Documented Investigation into any Unexpected Discrepancy 277
对任何意外差异的记录调查277

Complete Analytical Records from All Tests and Summaries of Results 277
所有测试的完整分析记录和结果摘要277

Quality and Retention of Raw Data (e.g., chromatographs and spectra) 278
原始数据（例如色谱仪和光谱）的质量和保留率278

Correlation of Result Summaries to Raw Data; Presence of Unused Data 278
结果摘要与原始数据的相关性;存在未使用的数据278

Adherence to an Adequate OOS Procedure which
遵守适当的 OOS 程序

Includes Timely Completion of the Investigation 278
包括及时完成调查 278

Adequate Reserve Samples; Documentation of Reserve Sample Examination 279
充足的储备样品;储备样品检验文件279

Stability Testing Program, including Demonstration of
稳定性测试计划，包括

Stability Indicating Capability of the Test Methods 279
测试方法的稳定性指示能力279

Examples of Significant and/or Trend of Deficiencies 279
显著和/或缺陷趋势的例子279

Recent Regulatory Findings 280
最近的监管调查结果280

Issues with Procedures for OOS 287
OOS287 程序的问题

Environmental Monitoring and Control Issues 288
环境监测及控制事宜288

Media Fill Observations 288
介质填充观察288

Reference 289
编号289

Evaluating Your Facility for Compliance 291
评估您的工厂的合规性291

Jeanne Moldenhauer
珍妮·莫尔登豪尔

Who Should Perform Assessments 292
谁应该进行评估292

Typical Assessment Procedures 292
典型评估程序292

Audit Preparation 292
审计准备292

During the Audit 293
审计期间293

Completing the Assessment 294
完成评估294

Assessment Report 294
评估报告294

Assessment Follow-Up 294
评估随访294

Retention of Assessment Reports 295
保留评估报告295

Example of an Audit Checklist 296
审计清单示例296

Preparing for an FDA Systems-Based Inspection 325
为 FDA 基于系统的检查做准备325

Jeanne Moldenhauer
珍妮·莫尔登豪尔

Why Prepare? 325
为什么要准备？325

Historical Methods Used for Inspection Preparation 326
用于检查准备的历史方法326

The Current Situation 327
现状327

Identify Key Employees and Train Them 328
识别关键员工并对其进行培训328

Interacting with the FDA During the Inspection 329
在检查期间与 FDA 互动329

What to Expect During the Interview Process 330
面试过程中会发生什么330

Aids to Training and Answering Questions During the Audit 330
审核期间培训和回答问题的辅助工具 330

History of Company and Organization Charts 330
公司和组织结构图的历史330

Flowcharts 331
流程图331

Sterile Process Validation Documentation Packages 332
无菌工艺验证文档包332

Key Indices 332
关键指数332

Standardization of Documentation 332
文档标准化332

Technical Glossary 332
技术词汇332

Questions to Ask the FDA 333
要向 FDA333 提出的问题

Information that Should be Conveyed to the Investigator 333
应传达给调查员的信息333

Practice Tours of the Facility 334
设施体验之旅334

Self-Audit and Know Your Vulnerabilities 334
自我审计并了解您的漏洞334

Prepare for the FDA Areas of Focus 335
为 FDA 重点领域做好准备335

Inspectional Guidance Documents 335
检验指导文件335

Know Your Company’s Policies 336
了解公司的政策336

Documentation 336
文档336

Requests for Samples 337
索取样品337

Mock Inspections 338
模拟检查338

I Know I Have a Problem. Now What? 338
我知道我有问题。现在怎么办？338

Simple Rules of Etiquette to Use During an Inspection 339
检查时使用的简单礼仪规则339

Handling Difficult Investigators 340
处理难缠的调查员340

Learn from the Mistakes of Others 341
从他人的错误中吸取教训341

Observations for the Quality System 341
对质量体系的观察341

Observations for the Laboratory System 342
实验室系统的观察结果342

Observations for the Facilities and Equipment System 342
对设施和设备系统的观察342

Observations for the Production System 342
对生产系统的观察342

Acknowledgements 343
致谢343

References 343
参考资料343

Managing of Regulatory Inspections 347
监管检查管理347

Jeanne Moldenhauer
珍妮·莫尔登豪尔

Who May Inspect the Facility? 347
谁可以检查设施？347

What Requirements Allow the Government Inspection? 348
哪些要求允许政府检查？348

What is the Purpose of the Audit? 349
审计的目的是什么？349

Are There Company Policies or Procedures that will Define
是否有公司政策或程序将定义

What Investigators May Do During the Inspection? 350
调查员在检查期间可以做什么？350

What’s Your Job? 351
你的工作是什么？351

How Do I Handle Documentation? 353
如何处理文档？353

What Could Go Wrong? 353
会出什么问题？353

Conclusion 353
结论353

Acknowledgements 353
鸣谢353

Concluding an Inspection and Handling Inspection Findings 355
完成检查和处理检查结果355

Jeanne Moldenhauer
珍妮·莫尔登豪尔

The Exit Discussion 356
退出讨论356

Reporting of Observations, the FDA-483 357
观察报告，FDA-483357

General Principles for FDA-483 Observations 357
FDA-483 观察的一般原则357

Annotation of Observations 358
观察注释358

Impact of these Observations 358
这些观察的影响358

Freedom of Information (FOI) 359
信息自由 （FOI）359

Writing Observations 359
写作观察359

Triggers to Observations 359
观察的触发因素359

Non-reportable Observations 360
不可报告的观察结果360

Determining the Significance of FDA-483 Observations 360
确定 FDA-483 观察结果的重要性360

Handling Adverse Findings 361
处理不良发现361

Written Response to the FDA-483 361
对 FDA-483361 的书面回复

Dispute Resolution 362
争议解决362

Evaluate Compliance with Corrective Action Program Established 363
通过制定的纠正行动计划363 评估合规性

Warning Letters 363
警告信363

On-going Evaluations 363
持续评估363

References 364
参考资料364

Glossary 365
词汇表365

Author Biographies 377
作者简介377

List ofTables
Table 列表

Table 4.1 Quality System — Management Responsibility 84
表 4.1质量体系 — 管理责任84

Table 4.2 Quality System — Drug Product Reviews
表 4.2质量体系 — 药品审查

21 CFR211.180(e) 89
《美国联邦法规》第 21 卷第 211.180（e） 条89

Table 4.3 Quality System — Drug Product Complaints 99
表 4.3质量体系 — 药品投诉99

Table 4.4 Quality System — Discrepancy and Failure
表 4.4质量体系 — 差异和失败

Investigations 21 CFR 211.22 and 21 CFR 211.192 106
调查 21 CFR 211.22 和 21 CFR 211.192106

Table 4.5 Quality System — Change Control 21 CFR 211.22(c) 116
表 4.5质量体系 — 变更控制 21 CFR 211.22（c）116

Table 4.6 Quality System — Product Improvement Projects 121
表 4.6质量体系 — 产品改进项目121

Table 4.7 Quality System — Reprocess/Rework 21 CFR 21 l.l 15 125
表 4.7质量体系 — 再加工/返工 21 CFR 21 l.l 15125

Table 4.8 Quality System — Drug Product Returns and Salvaging
表 4.8质量体系 — 药品退货和回收

21 CFR 211.204,21 CFR 211.208 131
《美国联邦法规》第 21 卷第 211.204 卷，《美国联邦法规》第 21 卷第 211.208131 卷

Table 4.9 Quality System — Rejects 21 CFR 211.89,
表 4.9 质量体系 — 拒绝 21 CFR 211.89，

21 CFR 211.122,21 CFR 211.165 136
《美国联邦法规》第 21 卷第 211.122 卷，《美国联邦法规》第 21 卷第 211.165136 卷

Table 4.10 Quality System — Stability Testing Program
表 4.10 质量体系 — 稳定性测试程序

21 CFR 211.166 142
《美国联邦法规》第 21 卷第 211.166142 卷

Table 4.11 Quality System — Quarantine Control System
表 4.11 质量体系 — 检疫控制体系

21 CFR 211.80,21 CFR 211.82,21 CFR 211.89,
21 CFR 211.80,21 CFR 211.82,21 CFR 211.89，

21 CFR2I l.l 10,21 CFR 211.142 148

Table 4.12 Quality System —Validation and Revalidation 154
表 4.12 质量体系 — 验证和重新验证154

Table 4.13 Quality System —Training and Qualification of
表 4.13 质量体系 — 培训和资格认证

Quality Unit Employees 21 CFR 211.25 161
质量单位员工 21 CFR 211.25161

Table 6.1 Adhesion of Microorganisms and Biofilm Formation at Various Levels of Wall Shear Stress in Sanitary Stainless Steel OD Tubing 222
表 6.1 卫生级不锈钢外径管中不同水平壁剪切应力下微生物的粘附和生物膜形成222

Table 6.2 Economic Design Flow Rates and Velocities for
表 6.2 经济设计流速和速度

Sanitary Tubing (best and worse case conditions) 222
卫生级管材（最佳和最差情况）222

List of Figures
图表列表

Figure I. I Example of FDA Form 2656 used for Drug
图 I.I 用于药物的 FDA 表格 2656 示例

Establishment Registration 4
场所登记4

Figure 1.2 Example of FDA Form 2657 used for Drug
图 1.2 用于药物的 FDA 表格 2657 示例

Product Listing FDA’s Electronic Forms,
产品列表 FDA 的电子表格，

Numerical Listing 6
数值列表6

Figure 5.1 Raw Material Flow 172
图 5.1原料流向172

Figure 5.2 Finished Product Flow 173
图 5.2成品流向173

Figure 5.3 Component Flow Diagram 174
图 5.3组件流程图174

Figure 5.4 Prefilters Installed in Air Handler 183
图 5.4AirHandler183 中安装的预过滤器

Air Flows from Room Ceiling Air Supply to
空气从房间天花板送风流至

Low Wall Returns 184
低壁回波184

Ductwork Connection to Low Wall Return
管道系统连接到低墙回水

Termination Point 185
终止点185

Rooftop Air Handler with Fresh Air Intake 187
带新鲜空气进气口的屋顶空气处理器187

Figure 6.1 Typical Pharmaceutical Water Use Point 224
图 6.1典型的制药用水点224

Figure 11.1 FDA Form 484 345
图 11.1FDA 表格 484345

I

INTRODUCTION
介绍

Jeanne Moldenhauer
珍妮·莫尔登豪尔

Vectech Pharmaceutical Consultants, Inc.

Farmington Hills, Ml
法明顿希尔斯 （Farmington Hills， Ml）

Training of new employees in a pharmaceutical company almost always includes instilling a “healthy fear” of inspections conducted by regulatory agencies. Most, if not all, countries in the world have governmental agencies responsible for the safety and efficacy of the medicines manufactured, sold, and distributed within their country. These agencies typically have the legal authority to go into the production facilities to assess the various aspects of the manufacturing and distribution facility. As such, employees learn that the company’s viability is dependent upon successfully passing these inspections.
对制药公司新员工的培训几乎总是包括灌输对监管机构进行的检查的“健康恐惧”。世界上大多数（如果不是全部）国家都有政府机构负责在本国生产、销售和分销的药物的安全性和有效性。这些机构通常拥有进入生产设施以评估制造和分销设施各个方面的合法权力。因此，员工了解到公司的生存能力取决于成功通过这些检查。

Passing the inspection is a qualitative objective. Consider the case of a student in school, who is graded on his or her performance. Typical grading systems go from “A” to “B” to “C” to “D” to “Failing”, with “A” being the highest level and “D” being the lowest level of passing performance. For some students, straight “As” are the only acceptable level of performance. Other students are satisfied with all grades being at least a “C”. In other cases, as long as a pass grade is obtained, this is considered acceptable. Companies may have similar attitudes regarding regulatory inspections. One may find a company with expectations of no adverse observations by a regulatory agency during an inspection. Another company may be satisfied to have some observations, and may have some general idea of how many observations are considered acceptable, for example, fewer than 10 observations are a good inspection. Still others may feel that anything is
通过检查是一个定性目标。考虑一下学校里的一个学生的情况，他或她的表现是被评分的。典型的评分系统从“A”到“B”到“C”到“D”到“不及格”，其中“A”是最高级别，“D”是最低级别的及格表现。对于一些学生来说，全 “A” 是唯一可以接受的表现水平。其他学生对所有成绩都至少为“C”感到满意。在其他情况下，只要获得及格成绩，就被认为是可以接受的。公司可能对监管检查持类似态度。人们可能会发现一家公司期望监管机构在检查期间不会有不利的观察。另一家公司可能对有一些观察结果感到满意，并且可能对多少观察值被认为是可接受的有一些大致的了解，例如，少于 10 个观察值就是一个很好的检查。还有一些人可能觉得任何事情都是